Biology subjects

Vargas-Garcia, C. A.

Publications and source records attributed to Vargas-Garcia, C. A..

5 recordsLinked to original sources

bioRxiv2024

A Generalized Adder mechanism for Cell Size Homeostasis: Implications for Stochastic Dynamics of Clonal Proliferation

Measurements of cell size dynamics have revealed phenomeno-logical principles by which individual cells control their size across diverse organisms. One of the emerging paradigms of cell size homeostasis is the adder, where the cell cycle duration is established such that the cell size increase from birth to division is independent of the newborn cell size. We provide a mechanistic formulation of the adder considering that cell size follows any arbitrary non-exponential growth law. Our results show that the main requirement to obtain an adder regardless of the growth law (the time derivative of cell size) is that cell cycle regulators are produced at a rate proportional to the growth law and cell division is triggered when these molecules reach a prescribed threshold level. Among the implications of this generalized adder, we investigate fluctuations in the proliferation of single-cell derived colonies. Considering exponential cell size growth, random fluctuations in clonal size show a transient increase and then eventually decay to zero over time (i.e., clonal populations become asymptotically more similar). In contrast, several forms of non-exponential cell size dynamics (with adder-based cell size control) yield qualitatively different results: clonal size fluctuations monotonically increase over time reaching a non-zero value. These results characterize the interplay between cell size homeostasis at the single-cell level and clonal proliferation at the population level, explaining the broad fluctuations in clonal sizes seen in barcoded human cell lines.

systems biology↗

bioRxiv2022

Modeling cell size regulation under complex and dynamic environments

In nature, cells face changes in environmental conditions that can modify their growth rate. In these dynamic environments, recent experiments found changes in cell size regulation. Currently, there are few clues about the origin of these cell size changes. In this work, we model cell division as a stochastic process that occurs at a rate proportional to the size. We propose that this rate is zero if the cell is smaller than a minimum size. We show how this model predicts some of the properties found in cell size regulation. For example, among our predictions, we found that the mean cell size is an exponential function of the growth rate under steady conditions. We predict that cells become smaller and the way the division strategy changes during dynamic nutrient depletion. Finally, we use the model to predict cell regulation in an arbitrary complex dynamic environment.

systems biology↗

bioRxiv2022

Dynamic analysis of sequestration-based feedbacks in cellular and biomolecular circuits

Nonlinear feedback controllers are ubiquitous features of biological systems at different scales. A key motif arising in these systems is a sequestration-based feedback. As a physiological example of this type of feedback architecture, platelets (specialized cells involved in blood clotting) differentiate from stem cells, and this process is activated by a protein called Thrombopoietin (TPO). Platelets actively sequester and degrade TPO, creating negative feedback whereby any depletion of platelets increases the levels of freely available TPO that upregulates platelet production. We show similar examples of sequestration-based feedback in intracellular biomolecular circuits involved in heat-shock response and microRNA regulation. Our systematic analysis of this feedback motif reveals that platelets induced degradation of TPO is critical in enhancing system robustness to external disturbances. In contrast, reversible sequestration of TPO without degradation results in poor robustness to disturbances. We develop exact analytical results quantifying the limits to which the sensitivity to disturbances can be attenuated by sequestration-based feedback. Next, we consider the stochastic formulation of the circuit that takes into account low-copy number fluctuations in feedback components. Interestingly, our results show that the extent of random fluctuations are enhanced with increasing feedback strength, but can exhibit local maxima and minima across parameter regimes. In summary, our systematic analysis highlights design principles for enhancing the robustness of sequestration-based feedback mechanisms to external disturbances and inherent noise in molecular counts.

physiology↗

bioRxiv2021

Arf6 anchors Cdr2 nodes at the cell cortex to control cell size at division

Fission yeast cells prevent mitotic entry until a threshold cell surface area is reached. The protein kinase Cdr2 contributes to this size control system by forming multiprotein nodes that inhibit Wee1 at the medial cell cortex. Cdr2 node anchoring at the cell cortex is not fully understood. Through a genomic screen, we identified the conserved GTPase Arf6 as a component of Cdr2 signaling. Cells lacking Arf6 failed to divide at a threshold surface area and instead shifted to volume-based divisions at increased overall size. Arf6 stably localized to Cdr2 nodes in its GTP-bound but not GDP-bound state, and its GEF (guanine nucleotide exchange factor) Syt22 was required for both Arf6 node localization and proper size at division. In arf6{Delta} mutants, Cdr2 nodes detached from the membrane and exhibited increased dynamics. These defects were enhanced when arf6{Delta} was combined with other node mutants. Our work identifies a regulated anchor for Cdr2 nodes that is required for cells to sense surface area.

cell biology↗

bioRxiv2020

Cell size statistics in cell lineages and population snapshots with different growth regimes and division strategies.

Growing populations of bacteria control their growth and division reaching narrow distributions of cell-sizes. In this paper we explored how different combinations of growth regimes and division mechanisms lead to different cell-size statistics in these populations. Deterministic and stochastic modeling were used to describe the size distribution of a population of cells that is observed from two different perspectives: as single cell lineages, i.e. random paths in the lineage tree, or as snapshots, at given times, of a population in which all descendants of a single ancestor cell are observed. Our time-dependent approaches allowed us to obtain both the transient dynamics and the steady state values for the main statistical moments of the cell-size distribution. Also, we established mathematical relationships among the statistics in the two considered perspectives, thus improving our knowledge of how cells control their growth and proliferation.

systems biology↗